This invention relates to 3-acylated pyridoxal analogues and pharmaceutical compositions thereof and to treatments for cardiovascular and related diseases, for example, hypertrophy, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, heart failure subsequent to myocardial infarction, myocardial infarction, ischemia reperfusion injury, blood coagulation, platelet aggregation, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated; treatments for vitamin B6 deficiency and related diseases, for example, hyperhomocysteinemia; and treatments for melanoma and related diseases.
Pyridoxal-5xe2x80x2-phosphate (PLP), an end product of vitamin B6 metabolism, plays a vital role in mammalian health. Vitamin B6 typically refers to pyridoxine, which is chemically known as 2-methyl-3-hydroxy-4,5-di(hydroxymethyl)pyridine and is represented by formula I: 
Yet two additional compounds, pyridoxal of formula II 
and pyridoxamine of formula III 
are also referred to as vitamin B6. All three compounds serve as precursors to pyridoxal-5xe2x80x2-phosphate (PLP), which is chemically known as 3-hydroxy-2-methyl-5-[(phosphonooxy) methyl]-4-pyridine-carboxaldehyde and is represented by formula IV: 
PLP is the biologically active form of vitamin B6 inside cells and in blood plasma. Mammals cannot synthesize PLP de novo and must rely on dietary sources of the precursors pyridoxine, pyridoxal, and pyridoxamine, which are metabolized to PLP. For instance, mammals produce PLP by phosphorylating pyridoxine by action of pyridoxal kinase and then oxidizing the phosphorylated product. PLP can also be chemically synthesized by, for example, reacting ATP with pyridoxal, reacting phosphorus oxychloride with pyridoxal in aqueous solution, and reacting pyridoxamine with concentrated phosphoric acid and then oxidizing the phosphorylated product.
PLP is a regulator of biological processes and a cofactor in more than 100 enzymatic reactions. It has been shown to be an antagonist of a purinergic receptor, thereby affecting ATP binding; it has been implicated in modulation of platelet aggregation; it is an inhibitor of certain phosphatase enzymes; and it has been implicated in the control of gene transcription. PLP is also a coenzyme in certain enzyme-catalyzed processes, for example, in glycogenolysis at the glycogen phosphorylase level, in the malate asparatate shuttle involving glycolysis and glycogenolysis at the transamination level, and in homocysteine metabolism.
Mammals may have deficiencies in PLP synthesis or function because of inadequate dietary uptake of precursors or antagonism of PLP synthesis or PLP function as a coenzyme as a result of, for example, genetic defects or a drug binding to PLP to make an intermediate that inhibits an enzyme in the PLP metabolic pathway or a drug inhibiting another step in the synthesis of PLP. There are situations where high, sustained plasma levels of PLP can provide a desirable therapeutic effect, particularly with respect to cardiovascular health.
To boost mammalian PLP levels, lipophilic PLP precursors that are metabolized in vivo to PLP have been administered. Although the administration of some compounds have shown some therapeutic benefits, there have been disadvantages associated with the compounds disclosed to date, such as, for example, excretion, rapid or inefficient metabolism, and toxicity.
Thus, there is a need to identify and administer drugs that are readily absorbed and converted to PLP in the blood or inside cells; that more slowly metabolize to PLP in vivo to ultimately maintain sustained levels of PLP, to lessen loss by excretion, and to decrease the likelihood of neurotoxicity; or that beneficially affect PLP-related conditions.
The present invention provides for 3-acylated pyridoxal analogues. One embodiment of the invention includes a 3-acylated analogue of pyridoxal (2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine), which is a compound of formula V: 
or a pharmaceutically acceptable acid addition salt thereof; wherein
R1 is alkyl,
alkenyl,
in which alkyl or alkenyl can be interrupted by nitrogen, oxygen, or sulfur, and can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl,
aryloxy,
arylthio, or
aralkyl,
in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy.
Another embodiment of the invention is a 3-acylated analogue of pyridoxal-4,5-aminal (1-secondary amino-1,3-dihydro-7-hydroxy-6-methylfuro(3,4-c)pyridine), which is a compound of formula VI: 
or a pharmaceutically acceptable acid addition salt thereof; wherein
R1 is alkyl,
alkenyl,
in which alkyl or alkenyl can be interrupted by nitrogen, oxygen, or sulfur, and can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl,
aryloxy,
arylthio, or
aralkyl,
in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy; and
R2 is a secondary amino group.
In another aspect, the invention is directed to a pharmaceutical composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula V or VI.
The invention is also directed to a method of treating vitamin B6 deficiency and related diseases, for example, hyperhomocysteinemia, by administering a therapeutically effective amount of a compound of formula V or VI in a unit dosage form.
In another aspect, the invention is directed to a method of treating cardiovascular and related diseases, for example, hypertension, hypertrophy, arrhythmia, congestive heart failure, myocardial ischemia, heart failure subsequent to myocardial infarction, myocardial infarction, ischemia reperfusion injury, blood coagulation, platelet aggregation, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated by administering a therapeutically effective amount of a compound of formula V or VI in a unit dosage form. For such a method, a compound of formula V or VI can be administered alone or concurrently with a known therapeutic cardiovascular agent, for example, angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a vasodilator, a diuretic, an xcex1-adrenergic receptor antagonist, an antioxidant, or a mixture thereof.
In still another aspect, the invention is directed to a method of treating melanoma and related diseases by administering a therapeutically effective amount of a compound of formula V or VI in a unit dosage form. For such a method, a compound of formula V or VI can be administered alone or concurrently with known medicaments suitable for treating melanoma and related diseases, for example, interleukin-2 immunotherapy.